Postinduction Treatment of ALL

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric Treatment Editorial Board uses a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Consolidation/Intensification Therapy

Once remission has been achieved, systemic treatment in conjunction with central nervous system (CNS) sanctuary therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification following achievement of remission and before beginning maintenance therapy. Intensification may involve use of the following:

• Intermediate-dose or high-dose methotrexate (1–5 g/m²) with leucovorin rescue or escalating-dose methotrexate without rescue.[1,2,3,4]
• Drugs similar to those used to achieve remission (reinduction or delayed intensification).[1,5]
• Different drug combinations with little known cross-resistance to the induction therapy drug combination including cyclophosphamide, cytarabine, and a thiopurine.[6]
• L-asparaginase for an extended period of time.[4,7]
• Combinations of the above.[1,8,9]

Standard-risk ALL

In children with standard-risk acute lymphoblastic leukemia (ALL), there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[10,11,12] For example, regimens utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase) have been used with good results for children with standard-risk ALL.[2,3,11] Similarly favorable results for standard-risk patients have been achieved with regimens utilizing multiple doses of L-asparaginase (20–30 weeks) as consolidation, without any postinduction exposure to alkylating agents or anthracyclines.[7,13]

Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of delayed intensification improved outcome for children with standard-risk ALL treated with regimens using a German Berlin-Frankfurt-Muenster (BFM) backbone.[14,15,16] The delayed intensification phase on such regimens, including those of the Children's Oncology Group, consists of a 3-week reinduction (including anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 3 months after remission is achieved.[1,14,17] In a Children's Cancer Group (CCG) study for standard-risk ALL, which utilized dexamethasone for induction, a second delayed intensification phase provided no benefit in patients who were rapid early responders.[18]COG-1991 for NCI standard-risk patients compared escalating intravenous (IV) methotrexate in conjunction with vincristine versus a standard maintenance combination including oral methotrexate given during two interim maintenance phases. IV methotrexate produced a significant improvement in event-free survival (EFS), which was primarily a result of a decreased incidence of CNS relapse.[abstract]

High-risk ALL

In high-risk patients, a number of different approaches have been used with comparable efficacy.[7,19,20]; [17][Level of evidence: 2Di] Treatment for high-risk patients generally is more intensive than that for standard-risk patients, and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short- and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens. In a Dana-Farber Cancer Institute (DFCI) ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m² /dose to a cumulative dose of 300 mg/m²) or the same dose of doxorubicin with dexrazoxane during the induction and intensification phases of multiagent chemotherapy. Study results demonstrated that the use of the cardioprotectant dexrazoxane prior to doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk compared with the use of doxorubicin alone 5 years posttreatment. In addition, a greater long-term protective effect was noted in girls compared to boys.[21,22]

The former CCG developed an augmented BFM treatment regimen featuring repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and L-asparaginase during interim maintenance and additional vincristine/L-asparaginase pulses during initial consolidation and delayed intensification. Augmented therapy also included a second interim maintenance and delayed intensification phase. In the CCG-1882 trial, National Cancer Institute (NCI) high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy. The augmented therapy regimen produced a significantly better EFS compared with standard CCG modified BFM therapy.[23] In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.[24]

The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies as well as therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among rapid early responders. Augmented therapy was associated with an improvement in EFS; there was no benefit associated with the administration of the second interim maintenance and delayed intensification phases.[25][Level of evidence: 1iiA] Of note, there was a significant incidence of osteonecrosis of bone in teenaged patients who received the augmented-BFM regimen.[26]

Very high-risk ALL

Approximately 10% to 20% of patients with ALL are classified as very high risk, including infants, those with adverse cytogenetic abnormalities (e.g., t[9;22], t[4;11], or low hypodiploidy [<44 chromosomes]) and poor response to initial therapy (e.g., high end-induction minimal residual disease [MRD] or high absolute blast count after a 7-day steroid prophase).[17,27] Patients who fail induction therapy are also at very high risk of subsequent relapse even if they achieve complete remission. Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase, often including agents not typically used in frontline ALL regimens for standard- and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.[17] However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[17,28]

On some clinical trials, very high-risk patients have also been considered candidates for allogeneic stem cell transplantation (SCT) in first remission, [28,29,30] although it is not clear if outcomes are better with transplantation. In a European cooperative group study, very high-risk patients (defined as one of the following: morphologically persistent disease after a four-drug induction, t[9;22], t[4;11], or poor response to prednisone prophase in patients with either T-cell phenotype or presenting WBC >100,000/µL) were assigned to receive either an allogeneic SCT in first remission (based on the availability of a human lymphocyte antigen [HLA]-matched related donor) or intensive chemotherapy.[28] Using an intent-to-treat analysis, patients assigned to allogeneic SCT (on the basis of donor availability) had a superior 5-year disease-free survival (DFS) compared with those assigned to intensive chemotherapy (57% ± 7% for transplant versus 41% ± 3% for chemotherapy, P = .02); however, there was no significant difference in overall survival (OS) (56% ± 6% for transplant versus 50% ± 3% for chemotherapy, P = .12) . For patients with T- cell ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic SCT.[29] In another study of very high-risk patients, which included children with extremely high presenting leukocyte counts in addition to those with adverse cytogenetic abnormalities and/or initial induction failure (M2 marrow), allogeneic SCT in first remission was not associated with either a DFS or OS advantage.[30]

Maintenance Therapy

Backbone of maintenance therapy

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical trials generally call for giving oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS.[31] On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.[32]

Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[33,34] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[33,34] Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematopoietic toxicity than patients who are homozygous for the normal allele.[33]

The use of continuous 6-thioguanine (6-TG) instead of 6-mercaptopurine (6-MP) during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[35,36,37,38,39] Because of the risk of hepatic complications, 6-TG is no longer utilized in maintenance therapy in current protocols.

The Brazilian Childhood Cooperative group reported a variation in approach to maintenance therapy.[40][Level of evidence: 1A] In a cohort that was comprised of mostly lower-risk children, standard oral versus intermittent IV dosing of methotrexate (weekly vs. every three weeks) and 6-mercaptopurine (daily vs. 10 days on and 11 days off) was compared. Intermittently dosed medications were given at higher doses overall compared with standard dosing. In addition, boys on the protocol received only 2 years of therapy. A significant survival advantage was noted in boys receiving intermittent dosing, while the outcome with girls was equivalent. Because of differences in risk classification and OS rates slightly lower than reported by other groups, it is difficult to know whether the benefits this approach offered to boys would apply in other settings.

Vincristine/corticosteroid pulses

Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of intensive, multiagent regimens remains controversial.

A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients receiving monthly vincristine/prednisone pulses,[41] and a meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[42,43] However, a systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy.[43]

In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[44] However, a small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In that study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[45][Level of evidence: 1iiA]

When steroid pulses are used during the maintenance phase, dexamethasone is preferred over prednisone for younger patients based on data from a CCG study, in which dexamethasone was compared with prednisone for children aged 1 to 9 years with lower-risk ALL.[14,46] On that trial, patients randomized to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.[14,46] In a Medical Research Council trial comparing dexamethasone versus prednisolone during induction and maintenance therapies in both standard-risk and high-risk patients, the EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.[47] The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.[26,48]

Duration of maintenance therapy

Maintenance chemotherapy generally continues until 2 to 3 years of continuous complete remission. On some studies, boys are treated longer than girls;[14] on others, there is no difference in the duration of treatment based on gender.[7,17] It is not clear that longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[17][Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.[42]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk for treatment failure. The Cellular Classification and Prognostic Variables section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.

COG studies for standard-risk ALL

The COG recently opened a new trial for NCI standard-risk patients (COG-AALL0932 [Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL]). Patients receive a three-drug induction with dexamethasone, vincristine, and IV PEG-L-asparaginase. Patients are assigned to various postinduction treatments based on assessment of day 8 peripheral blood MRD, end-induction marrow MRD, and cytogenetics. No assessment of morphologic early response is performed.

• Standard Risk – Low: Patients are included if they have day 8 peripheral blood MRD less than 0.01%, day 28 marrow MRD less than 0.01% and either t(12;21) or hyperdiploidy with additional copies of chromosomes 4 and 10 (favorable cytogenetics). Patients are randomly assigned to receive one of two postinduction treatments. The first treatment is POG-9404 therapy which includes a consolidation phase of six courses of IV methotrexate with leucovorin, oral 6-mercaptopurine, and intermittent dexamethasone and vincristine pulses. Patients do not receive a delayed intensification phase but proceed directly to maintenance, in which vincristine/dexamethasone pulses are given every 16 weeks. The second treatment is the standard arm of the COG-1991 study, which includes IV methotrexate without rescue in each of two interim maintenance phases, a standard reinduction, reconsolidation including doxorubicin, cyclophosphamide, and cytarabine, and maintenance with vincristine/dexamethasone pulses given every 12 weeks. Both regimens are expected to produce an EFS of approximately 95%.
• Standard Risk – Average: All patients will have end-induction MRD less than 0.01%. This stratum will include patients with favorable cytogenetics and day 8 peripheral blood MRD greater than 0.01% and patients with favorable and unfavorable cytogenetics with less than 1% MRD in peripheral blood on day 8. Patients will be randomly assigned to receive either 20 mg/m² or 40 mg/m² of oral methotrexate during maintenance and every 4-week versus every 12-week pulses of vincristine and dexamethasone. Backbone therapy will consist of the IV methotrexate arm of COG-1991.
• Standard Risk – with Down syndrome: NCI standard-risk patients with Down syndrome who show less than 0.01% MRD on day 28, regardless of day 8 peripheral blood MRD and cytogenetics, will receive post induction treatment on a separate arm of the trial.

All other patients who do not meet the above criteria will go off study at the end of induction and receive treatment at the discretion of the individual investigator. When the new COG high-risk study opens, such patients will be treated on that protocol.

Other studies

• Total XVI study (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): A study at St. Jude Children's Research Hospital is randomly assigning patients to receive either standard-dose (2,500 u/m²) or high-dose (3,500 u/m²) PEG-L-asparaginase during postremission therapy.
• DFCI-05001 (NCT00400946)(Treatment of ALL in Children): A DFCI Consortium protocol is comparing the relative efficacy and toxicity of IV PEG-L-asparaginase with intramuscular E. coli asparaginase during postinduction consolidation for patients in all risk groups. This protocol is also testing whether an intensified consolidation including high-dose cytarabine and etoposide improves the outcome for very high-risk patients (patients with high MRD at the end of remission induction, MLL translocations, or hypodiploidy [<44 chromosomes]).

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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48. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19 (12): 3066-72, 2001.